Project Abstract Birth defects are a leading cause of infant mortality, morbidity and healthcare costs in the United States, yet the etiology of most birth defects remains unknown. Continued progress toward lessening the public health impact of birth defects can be facilitated by population-based epidemiologic research aimed at identifying modifiable lifestyle, environmental and genetic factors that contribute to the risk for specific birth defects. Since 1996, the Centers for Birth Defects Research and Prevention (CBDRP) across the nation, funded by the CDC's National Center on Birth Defects and Developmental Disabilities, have collaborated on the National Birth Defects Prevention Study (NBDPS). The NBDPS was a population-based, multi-center case-control study which provided an unprecedented opportunity to assess the potential association between a variety of maternal exposures during early pregnancy and specific major, structural birth defects. Using the NBDPS research experience as a foundation from which to innovate, the new Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) will delve further into several promising areas of birth defects research that have maximum potential for translation to birth defects prevention efforts. The North Carolina Center for Birth Defects Research and Prevention (NCCBDRP) was established in Fall 2002 and has been a major contributor to the collaborative data collection and research enterprise of the NBDPS. The NCCBDRP is a collaborative effort between the Department of Epidemiology at the University of North Carolina Gillings School of Global Public Health in Chapel Hill, NC (UNC), and the North Carolina Birth Defects Monitoring Program (NCBDMP) at the North Carolina Division of Public Health in Raleigh, NC. The NCCBDRP has established an outstanding and unique infrastructure to implement the BD-STEPS protocol and to conduct high quality epidemiologic and other research focused on the causes and prevention of birth defects. We have assembled an impressive team of investigators and staff to contribute to the national study design, contribute scientifically defensible and high quality data and specimen collection, and provide scientific oversight. Historically, the NCCBDRP has provided critical assistance and leadership to the NBDPS in many areas including epidemiology, biostatistics, method development and pilot design, genetics, study conduct, and quality control for interviewing and laboratory procedures. We are very well positioned to implement the new BD-STEPS protocol as well as to conduct innovative and collaborative research. The purpose of BD-STEPS is to identify modifiable maternal exposures in early pregnancy that may increase the risk for having a pregnancy affected by certain major, structural birth defects. The specific aims of the NCCBDRP are to (1) Implement the standardized BD-STEPS protocol as the NC BD-STEPS, including (a) use the NC birth defects surveillance system to identify 244 cases (among livebirths, stillbirths and induced abortions) in the study area each year with one or more of the 17 birth defects included in the study protocol; (b) identify a random sample of 96 control infants per year using birth certificates; (c) conduct clinical review for case classification and confirmation using abstracted medical records and other information;(d) conduct all advance and follow-up mailings to potential participants including kits for self- collection of saliva, and provide contact information to the central interviewing agency; (e) obtain consent from participants to abstract medical records; and (f) obtain residual newborn blood spots from the North Carolina State Laboratory. (2) Provide substantive expertise for the innovative design of BD-STEPS interview questions, survey methods and novel study instruments including targeted online modules related to early pregnancy exposures such as diet, obesity, physical activity, infertility, occupation and chronic medical conditions; (3) Develop innovative study questions and proposals using BD-STEPS and NBDPS data to identify modifiable risk factors for birth defects with maximum potential for public health impact, analyze genetic factors, conduct rigorous analyses, present findings at national meetings, and publish at least 10 papers during the 5-year award period; (4) Provide expertise on epidemiologic and biostatistical methods such as bias analysis, missing data, correlated exposures, pooled samples, approaches for the analysis of gene sets, multiple SNPs, haplotypes, GWAS and epigenetics; (5) Conduct innovative laboratory research to develop innovative methods for using dried blood spots to investigate potential risk factors for birth defects including toxic metals and other exposures; (6) Participate in collaborative activities and research initiatives with other CBDRP and the CDC; and (7) Continue to train junior researchers in the field of birth defects epidemiology. By including multiple study sites, BD-STEPS will aim for a study population that is representative of the US population in racial/ethnic composition. The project period is anticipated to be 8/1/2013 - 7/31/2018.